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Relative contribution of changes in sodium current versus intercellular coupling on reentry initiation in 2-dimensional preparations of plakophilin-2-deficient cardiac cells.

ABSTRACT: Loss of expression of the desmosomal protein plakophilin-2 (PKP2) leads to decreased gap junction-mediated (GJ) coupling, and alters the amplitude and kinetics of sodium current in cardiac myocytes. Whether these modifications, alone or in combination, are sufficient to act as arrhythmogenic substrates remains undefined.This study sought to characterize arrhythmia susceptibility and reentry dynamics consequent to loss of PKP2 expression, and to assess the relative contribution of cell uncoupling versus alterations in sodium current in generation of reentry.Monolayers of neonatal rat ventricular myocytes were treated with oligonucleotides that either prevented or failed to prevent PKP2 expression. Numerical simulations modeled experimentally observed modifications in I(Na), GJ coupling, or both (models PKP2-Na, PKP2-GJ, and PKP2-KD, respectively). Relative roles of sodium current density versus kinetics were further explored.Loss of PKP2 expression increased incidence of rotors and decreased frequency of rotation. Mathematical simulations revealed that single premature stimuli initiated rotors in models PKP2-Na and PKP2-KD, but not PKP2-GJ. Changes in sodium current kinetics, rather than current density, were key to reentry initiation. Anatomical barriers led to vortex shedding, wavebreaks, and rotors when I(Na) kinetics, but not GJ coupling or I(Na) density, were altered.PKP2-dependent changes in sodium current kinetics lead to slow conduction, increased propensity to functional block, and vortex shedding. Changes in GJ or I(Na) density played only a minor role on reentry susceptibility. Changes in electrical properties of the myocyte caused by loss of expression of PKP2 can set the stage for rotors even if anatomical homogeneity is maintained.

SUBMITTER: Deo M

PROVIDER: S-EPMC3199345 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Relative contribution of changes in sodium current versus intercellular coupling on reentry initiation in 2-dimensional preparations of plakophilin-2-deficient cardiac cells.

Deo Makarand M Sato Priscila Y PY Musa Hassan H Lin Xianming X Pandit Sandeep V SV Delmar Mario M Berenfeld Omer O

Heart rhythm 20110701 11

<h4>Background</h4>Loss of expression of the desmosomal protein plakophilin-2 (PKP2) leads to decreased gap junction-mediated (GJ) coupling, and alters the amplitude and kinetics of sodium current in cardiac myocytes. Whether these modifications, alone or in combination, are sufficient to act as arrhythmogenic substrates remains undefined.<h4>Objective</h4>This study sought to characterize arrhythmia susceptibility and reentry dynamics consequent to loss of PKP2 expression, and to assess the rel ...[more]

PMID: 21723844

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Project description:In mammals, the suprachiasmatic nucleus (SCN) is the central pacemaker organizing circadian rhythms of behavior and physiology. At the cellular level, the mammalian clock consists of autoregulatory feedback loops involving a set of "clock genes," including the Cryptochrome (Cry) genes, Cry1 and Cry2. Experimental evidence suggests that Cry1 and Cry2 play distinct roles in circadian clock function. In mice, Cry1 is required for sustained circadian rhythms in dissociated SCN neurons or fibroblasts but not in organotypic SCN slices or at the behavioral level, whereas Cry2 is not required at any of these levels. It has been argued that coupling among SCN cellular oscillators compensates for clock gene defects to preserve oscillatory function. Here we test this hypothesis in Cry1(-/-) mice by first disrupting intercellular coupling in vivo using constant light (resulting in behavioral arrhythmicity) and then examining circadian clock gene expression in SCN slices at the single cell level. In this manner, we were able to test the role of intercellular coupling without drugs and while preserving tissue organization, avoiding the confounding influences of more invasive manipulations. Cry1(-/-) mice (as well as control Cry2(-/-) mice) bearing the PER2::LUC knock-in reporter were transferred from a standard light:dark cycle to constant bright light (~650 lux) to induce arrhythmic locomotor patterns. In SCN slices from these animals, we used bioluminescence imaging to monitor PER2::LUC expression in single cells. We show that SCN slices from rhythmic Cry1(-/-) and Cry2(-/-) mice had similarly high percentages of functional single-cell oscillators. In contrast, SCN slices from arrhythmic Cry1(-/-) mice had significantly fewer rhythmic cells than SCN slices from arrhythmic Cry2(-/-) mice. Thus, constant light in vivo disrupted intercellular SCN coupling to reveal a cell-autonomous circadian defect in Cry1(-/-) cells that is normally compensated by intercellular coupling in vivo.

Dataset Information

Relative contribution of changes in sodium current versus intercellular coupling on reentry initiation in 2-dimensional preparations of plakophilin-2-deficient cardiac cells.

Publications

Relative contribution of changes in sodium current versus intercellular coupling on reentry initiation in 2-dimensional preparations of plakophilin-2-deficient cardiac cells.

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